Background: Identifying the risk factors associated with a bone stress injury (BSI), including stress reactions and stress fractures, may aid in targeting those at increased risk and in formulating prevention guidelines for exercising girls and women. Purpose: To evaluate the effect of single or combined risk factors as defined by the female athlete triad—a syndrome involving 3 interrelated spectrums consisting of energy availability, menstrual function, and bone mass—with the incidence of BSIs in a multicenter prospective sample of 4 cohorts of physically active girls and women. Study Design: Cohort study; Level of evidence, 3. Methods: At baseline, participants’ (N = 259; mean age, 18.1 ± 0.3 years) anthropometric characteristics, eating attitudes and behaviors, menstrual function, sports participation or exercise activity, and pathological weight control behaviors were assessed. Dual-energy x-ray absorptiometry (DXA) measured the bone mass of the whole body, total hip, femoral neck, lumbar spine, and body composition. Participants were followed prospectively for the occurrence of injuries; those injuries confirmed by a physician were recorded. Results: Twenty-eight participants (10.8%) incurred a BSI. Forty-six percent of those who had ≥12 h/wk of purposeful exercise, a bone mineral density (BMD) Z score <–1.0, and who exhibited 3 to 4 of the following: BMI <21.0 kg/m2, oligo- or amenorrhea, elevated dietary restraint, and/or participation in a leanness sport exercise/activity at baseline, incurred a BSI during the prospective study period. Single factors significantly (P < .05) associated with the development of a BSI included ≥12 h/wk of purposeful exercise (14.7%), BMI <21.0 kg/m2 (15.3%), and low bone mass (BMD Z score <–1.0; 21.0%). The strongest 2- and 3-variable combined risk factors were low BMD (Z score <–1.0) + ≥12 h/wk of exercise, with 29.7% incurring a BSI (odds ratio OR, 5.1; 95% CI, 2.2-12.1), and ≥12 h/wk of exercise + leanness sport/activity + dietary restraint, with 46.2% incurring a BSI (OR, 8.7; 95% CI, 2.7-28.3). Conclusion: In the sample, which included female adolescents and young adults participating in competitive or recreational exercise activities, the risk of BSIs increased from approximately 15% to 20% for significant single risk factors to 30% to 50% for significant combined female athlete triad–related risk factor variables. These data support the notion that the cumulative risk for BSIs increases as the number of Triad-related risk factors accumulates.